Project Summary/Abstract Asthma therapy costs 56 billion dollars each year and over 8% of Americans, especially African Americans, American Indians, and Native Hawaiians, have asthmatic conditions. About 1.25 million Americans with severe asthma do not respond to the existing medications which are mainly providing symptomatic relief and fail to address the underlying pathogenic pathways. Therefore, new therapies targeting crucial pathways involved in asthma progression are urgently needed to effectively treat severe asthma and improve the quality of life for people with severe asthma. The long-term goal is to understand the impact of novel receptor guided delivery of siRNA using nanocarriers for targeting crucial pathways involved in asthma and to develop novel treatment strategies for severe asthma. STAT6 (signal transducer and activator of transcription 6) is an essential transcription factor in asthma progression via T helper 2 (Th2) cells, B cells, and airway epithelial cells. Currently, no STAT6 inhibitors are approved by the FDA, and the use of preclinical STAT6 inhibitors has been limited due to poor efficacy. The major limitations of translating naked siRNA to the clinical use are in vivo degradation and poor cell penetration. Targeted multimodal nanocarriers hold great promise for siRNA delivery; however, the potential of such modalities for asthma treatment are underexplored. The objective of this application is to develop receptor guided STAT6 siRNA nanocarriers using targeting peptide and bio- inspired polymeric materials capable of inhibiting STAT6 mediated responses in the Th2, B, and airway epithelial cells to enhance the anti-asthmatic efficacy with minimal side?effects. The central hypothesis of the proposed research is that that the IL4R? guided delivery of STAT6 siRNA loaded bio-inspired nanocarriers will deliver siRNA simultaneously to the cells at different locations involved in severe asthma in a targeted fashion, thereby effectively attenuating asthma. The delivery of STAT6 siRNA via the targeted nanocarrier is expected to target underlying key elements involved in asthma, achieve specific silencing and thereby improve the management of severe asthma. In aim #1, we will investigate the receptor guided targeted STAT6 siRNA loaded nanocarriers on established primary human and murine cells. In aim #2, we will first study the maximum tolerable dose followed by plasma kinetics and biodistribution of the targeted nanocarriers. Furthermore, we will test the dose-dependent efficacy of nanocarriers in an acute asthma model. This innovative strategy has great potential for the treatment of severe asthma and is expected to have a significant impact on asthma management. This will pave the way for targeted delivery of not only STAT6 siRNA but also for other anti- inflammatory agents. Through this highly meritorious project, we will train the next-generation of undergraduate and graduate students.